N-oxides of aminoalkylene-dibenzo(a d)cycloheptenes and the salts thereof

ABSTRACT

1-HALO-5-(3-DIMETHYLAMINOPROPYL OR PROPYLIDENE)-5HDIBENZO(A,D)CYCLOHEPTENE N-OXIDES, PREPARED, INTER ALIA, FROM THE CORRESPONDING 1-HALO-5-(3-DEMETHYLAMINOPROPYL OR PROPYLIDENE) - 5H -DIBENZO(A,D)CYCLOHEPTENES, ARE DESCRIBED. THE END PRODUCTS ARE USEFUL ANTIDEPRESSANTS.

UnitedStates Patent N-OXIDES OF AMINOALKYLENE-DIBENZO[a,d].CYCLQHEPTENES AND THE SALTS THEREOF Emilio Kyburz, Reinaclnand HansSpiegelberg, Basel, Switzerland, assignors to Hoffmann-La Roche Inc.,

'Nutley, NJ;

No Drawing; liiledMar. 12, 1969, Ser. No. 806,701 Claimspri0rity,'applicafion Switzerland, Mar. 20, 1968, 4,201/68 Int. Cl. C07c87/02 Cl. 260--570.8 TC 14 Claims ABSTRACT OF THE DISCLOSURE 1halo-,S-(idimethylaminopropyl or-propy1idene)-5H-dibenzo[a,d]cycloheptene N-oxides, prepared, inter alia, from thecorresponding l-halo-S-(3-dimethylaminopropyl orpropylidene) 5Hdibenzo[a,d]cycloheptenes,are described. The end products are usefulantidepressants.

BRIEF SUMMARY OF THE INVENTION The invention relates to tricycliccompounds of the formulas R i R X\ I /X I a I t\ I Ia Ib wherein R ischlorine or fluorine and X is ethylene or vinylene, and theirstereoisomers and pharmaceutically acceptable acid addition salts. Thecompounds of formulas Ia and 1b are'useful antidepressant agents. I

In another aspect, the invention'relates to intermediates and processes.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to tricycliccompounds of the formulas "and CH CH Y 3 y 3 HOHZCHZN omomonm 0 on, ii011 wherein R is chlorine or fluorine and X is ethylene orvinylene,

and their stereoisomers and pharmaceutically acceptable acid additionsalts. The compounds of Formulas Ia and lb possess high antidepressiveaction and low toxicity, and are distinguished by the absence or onlyinsignificant antichlorinergic action, which is particularlyadvantageous. Furthermore, the compounds of Formulas Ia and lb aredistinguished by various actions on the nervous system, for example,narcosis-potentiating. adrenolytis,,sedative, antihistamine-like andlocal anesthetic actions.

,In, the above Formulas Ia and Ib, R preferably is chlorine.Representatives of the compounds of Formulas Ia and lb are,,for.example: a

1 3,641,153 Patented Feb. 8, 1972 1-chloro-5-(3-dimethylaminopropylidene)-5H-dibenzo- [a,d] cycloheptene N-oxide; Il-chloro- 10,1 l-dihydro-S- (3-dimethylaminopropylidene)SH-dibenzo[a,d]cycloheptene N-oxide; 1-chloro-5-(S-dimethylaminopropyl)-5H-dibenzo[a,d]-

cycloheptene N-oxide; 1-chloro-10,1 1-dihydro5-(S-dimethylaminopropyl)-(5H- dibenzo[a,d]cycloheptene N-oxide; and the like.

Particularly interesting isl-chloro-S-(B-dimethylaminopropylidene)-5H-dibenzo[a,d]cyclohepteneN-oxideQ The present invention relates to the tricyclic cornpounds' ofFormulas Ia and Ib, their isomers and pharmaceutically acceptable acidaddition salts, as well as intermediates andprocesses.

A process of the invention for preparing the tricyclic compounds ofFormula Ia and Ib comprises oxidizing a compound of the formula IIbwherein R and X are as previously described.

Another process comprises dehydrating a compound of the formula whereinR. and X are as previously described and one of the symbols Y and Y ishydrogen and the other is hydroxyl,

or an acid addition salt thereof.

Still another process comprises reacting a compound of the formulawherein R and X are as previously described; Z is a halogen or asubstituted sulfonyloxy residue and A is the anion of an acid,

with dimethylhydroxylamine.

, 3 A still further process comprises reacting a compound of the formulaVIIe.

wherein R and X are as previously described,

with a methylating agent.

In the aforementioned processes, in any desired sequence, the isomersare isolated from an isomer mixture obtained, if desired, and a baseobtained is converted into a pharmacentically acceptable acid additionsalt, if desired.

According to a'preferred process embodiment of the invention, a tertiaryamine of the Formula I'Ia or III) is oxidized. As the oxidizing agent,there can be utilized organic peroxides, for example, monosubstitutedorganic peroxides such as C -C alkyl or alkanoyl hydroperoxides, such ast.butyl hydroperoxide, performic acid, peracetic acid, and the like;phenyl-substituted derivatives of these hydroperoxides, such as cumolhydroperoxide, perbenzoic acid, and the like. The phenyl substitutentcan be substituted, if desired, with, for example, C -C alkyl or alkoxy,halogen or carboxy groups, exemplary of such compounds are4-methylperbenzoic acid, 4-methoxyperbenzoic acid, 3-chloroperbenzoicacid, monoperphthalic acid, and the like. Inorganic oxidizing agents canalso be used, for example, hydrogen peroxide; ozone; hypochlorites, suchas sodium, potassium or ammonium hypochlorite; peroxymonoandperoxydisulfuric acid. The use of hydrogen peroxide is preferred.Advantageously, the oxidation is effected in a solvent such as, forexample, methanol, ethanol, ether, benzene or chloroform and at atemperature in the range of between about -50 C. and +100 C. After aconventional working up, with the removal of the excess oxidizing agent,the corresponding N-oxide of Formula Ia or Ib is obtained. The latter isconveniently recovered in the form of an acid addition salt.

The tertiary amine of Formula Ila or IIb employed in the above reactioncan be prepared according to various methods. An exocyclicallyunsaturated amine of Formula Ha is conveniently prepared as follows:

l-chloro (or fluoro -5H-dibenzo [a,d] cyclohepten-S-one or thecorresponding 10,1l-dihydro compound is reacted with adimethylaminopropyl magnesium halide. After hydrolysis of the resultingaddition product, for example, with saturated ammonium chloridesolution, the S-carbinol obtained is dehydrated by heating with amineral acid, for example, with ethanolic hydrochloric acid whereby acompound of Formula IIa having an exocyclic double bond in the5-position is obtained.

The preparation of exocyclically saturated amines of Formula I-Ib iseffected, for example, as follows:

The S-carbinol obtained above is reduced with nascent hydrogen, forexample, zinc in glacial acetic, or with hydroiodic acid in the presenceof red phosphorus. Another method, which is particularly suitable forobtaining exocyclically saturated 10,l1-unsaturated amines of Formula11b is the following: 1-chloro(or fluoro)-5H-dibenzo[a,d]cycloheptene-S-one (or the corresponding 10,1l-dihydro compound) isreduced to the corresponding S-hydroxy compound by treatment with sodiumborohydride in dioxane-water; by treatment with a halogen halide, thelatter compound is converted into the corresponding S-halo compound,which can be converted to an exocyclically saturated compound of Formula11b, for example in ether, benzene or tetrahydrofuran and at boilingheat by reaction with a dimethylaminopropyl magnesium halide Accordingto a further process embodiment of the invention, a carbinol of FormulaIII is dehydrated. Preferred starting compounds of Formula III are thosein which Y is hydroxyl and Y is hydrogen.

The dehydration of compounds of Formula III leads to compounds ofFormula Ia having an exocyclic double bond in the 5-position. Thedehydration is conveniently carried out employing mineral acids such ashydrochloric or hydrobromic acid, in which case one can work in ananhydrous or aqueous medium. The dehydration is preferably carried outin ethanolic hydrochloric acid at a temperature in therange of betweenroom temperature and the boiling point of the reaction mixture, However,it also proceeds by heating, for example, at 50 C. to refluxtemperature, preferably at reflux temperature, with a high-boilinganhydrous solvent such as dimethyl sulfoxide. Other usual dehydratingagents can also be employed, for example, sulfuric acid, phosphorusoxychloride, zinc chloride or potassium bisulfate, for example, in aninert organic solvent, such as, chloroform or methylene chloride, at atemperature in the range of between room temperature and the boilingpoint of the reaction mixture.

Starting carbinols of Formula III wherein Y is hydroxyl and Y ishydrogen are obtainable by the oxidation of 1-chloro(orfluoro)-5-(S-dimethylaminopropyl)- 5 hydroxy 5H dibenzo[a,d]cyclohepteneor the corresponding 10,11-dihydro compound. The oxidation is effectedby treatment with any one of the oxidizing agents mentioned hereinabove,preferably by treatment with hydrogen peroxide in a solvent such asmethanol, ethanol, ether, benzene or chloroform, at about roomtemperature. After decomposition of the excess hydrogen peroxide with,for example, platinum black, the desired compound of Formula III can berecovered after evaporation of the solvent. The product can sometimes becrystallized by vigorous stirring, for example, at a temperature in therange of between about -20 and 0 C., and subsequently recovered bysimple filtration and rinsing.

Starting carbinols of Formula III wherein, on the other and, Y, ishydrogen and Y is hydroxyl are obtained, for example, by reacting acorresponding tricyclic S-ketone with ethyl magnesium bromide andhydrolyzing the reaction product. The resulting S-hydroxy-S-ethyl compound is dehydrated with acetyl chloride and subsequently treated withformic acid and hydrogen peroxide. The resulting5-hydroxy-5-(l-hydroxyethyl) compound is dehydrated to the correspondingS-acetyl compound with aqueous sulfuric acid. By treatment withformaldehyde and dimethylamine hydrochloride there is obtained a 5-dimethylaminopropionyl compound which is converted to the correspondingcarbinol by reduction with sodium borohydride. The reduction product issubsequently oxidized as described above for the preparation of thecarbinols of Formula III in which Y is hydroxyl and Y is hydrogen Afurther embodiment of the process of the invention comprises treating acompound of the Formulas IVa, IVb, V or V1 with dimethylhydroxylamine.

In the above Formula IVa or IVb, Z preferably is a chlorine or bromine.When Z is a substituted sulfonyloxy residue, preferably it is loweralkylsulfonyloxy residue, such as mesyloxy; phenylsulfonyloxy; loweralkylphenylsulfonyloxy residue, such as tosyloxy; or phenyl-(loweralky1)-sulfonyloxy residue, such as phenylmesyloxy. The anion A ofFormula V is preferably derived from an inorganic acid such ashydrochloric acid, hydrobrornic acid, hydroiodic acid, sulfuric acid orthe like.

The reaction of compounds of Formulas IVa, IVb, V and VI withdimethylhydroxylamine is preferably carried out in the presence of anexcess of dimethylhydroxylamine. Conveniently, the reaction can beconducted in the presence of a basic catalyst, for example, potassiumcarbonate,.sodium amide, potassium amide or the like. The reaction canbe effected in an organic solvent such as methanol, ethanol, acetone,benzene or toluene. While the reaction temperature is not critical, itconveniently can be in the range of between 0 C. and the boiling pointof the reaction mixture.

The starting compounds of Formula IVa or IVb may, for example, beobtained by reacting the corresponding tricyclic S-ketone with amethoxypropylmagnesium halide, with subsequent hydrolysis, reduction ordehydration of the resulting carbinol and treatment of theresultingmethoxypropylfidene) compound with an excess of a hydrohalicacid, for example, hydrobromic acid, to form the correspondinghalopropyl(idene) compound of Formula IVa or IVb. If themethoxypropyl(idene) compound is treated with dilute hydrohalic acid,the corresponding hydroxypropyl(idene) compound can be'recovered. Thelatter can be reacted with a substituted sulfonyl halide, for example,the chloride, to form a correspondingly substitutedsulfonyloxypropyl(idene) compound of Formula IVa or IVb. I

The quaternary salt of Formula V also employable as the startingmaterial, can be obtained by quaternization of the correspondingdimethylamino compound with amethylating agent such as methyl chloride,methyl bromide, methyl iodide or dimethylsulfate. The starting compoundof Formula VI is obtainable, for example, by the reaction of an allylGrignard compound with the corresponding tricyclic S-ketone andsubsequent hydrolysis and dehydration.

According to a further embodiment of a process of the invention, oneproceeds in such a way that a tricyclic hydroxyamine of Formula VIIa orVIIb is reacted with a methylating agent, such as, for example, acompound of the formula CH Z, wherein Z is halogen, preferably chlorine,bromine or iodine, or a substituted sulfonyloxy residue, for example, alower (cyclo-)alkylsulfonyloxy residue, such as mesyloxy,cyclopropylsulfonyloxy; phenylsulfonyloxy; a loweralkylphenylsulfonyloxy such as tosyloxy; or a phenyl-(loweralkyl)sulfonyloxy such as phenylmesyloxy. Dimethyl sulfate can also beused as the methylating agent. The reaction is conveniently elfected inthe presence of a polar solvent, for example, acetone, methanol,dimethylformamide and the like, at a temperature in the range of betweenabout C. and the boiling point of the reaction mixture.

,The starting tricyclic hydroxylamine of Formula VIIa or VIIb can, forexample, be obtained by the following reaction chain:

l chloro (or fluoro) H dibenzo[a,d]cyclohepten-S- one or thecorresponding 10,11-dihydro compound is reacted with amethylbenzylaminopropyl magnesium halide. After hydrolysis of theresulting addition product, for example, with saturated ammoniumchloride solution, the S-carbinol obtained is reacted with ethylchloroformate'. The 5-hydroxy-5-[3 (methyl-carbethoxyamino)-propyl]compound thus obtained is then hydrolyzed with an alkali, for example,by boiling with aqueous potassium hydroxide solution, whereby adecarboxylation occurs to form the corresponding5-hydroxy-5-(3-methylaminopropyl) compound. The latter can be reduced tothe corresponding S-(B-methylaminopropyl) compound by treatment withnascent hydrogen, for example, zinc in glacial acetic, or withhydroiodic acid in the presence of red phosphorus. If, on the otherhand, it is heated with a mineral acid, for example, with ethanolichydrochloric acid, the corresponding 5-(3-methylaminopropylidene)compound is formed. The reaction product is then oxidized in the mannerdescribed above, conveniently by treatment at about 0 C. with benzoylperoxide in an organic solvent such as ether or chloroform. Themethylbenzoyloxy-aminopropyl(-idene) compound thus obtained can beconverted into the desired tricyclic hydroxylamine' of Formula VIIa orVIIb by saponification with an alkali, for example, ethanolic causticpotash.

The methods given above for the preparation of starting compounds ofFormulas IIa, b-VIIa, b are only exemplary. Self-evidently, othermethods which are obvious to one skilled in the art can also beutilized. For example, Examples 8 and 9 hereinafter illustrate otherroutes to the starting compounds of Formula VIIa or VIIb The compoundsof Formulas Ia and lb which have an exocyclicdouble bond and/or a doublebond in the 10,11- position, and their salts, can be separated intotheir geometric isomers, i.e., 04- and ii-isomers. The methods ofseparation are known in the art. Preferably, the geometric isomers areseparated by fractional crystallization of the acid addition salts froma solvent, for example, acetone or from a solvent mixture, for example,methanol/diethyl ether.

The compounds of Formulas Ia and lb and their salts exist as racemates.A racemate can be separated into its optical isomers in a known manner,for example, by reaction with optically active acids such as tartaricacid or camphorsulfonic acid and subsequent crystallization.

The separation of the geometric and/or optical isomers can be undertakenat an intermediate product stage, so that in this way the process inaccordance with the invention is carried out with geometrically oroptically uniform starting materials of Formulas IIa b-VIIa, b.

The compounds of Formula Ia and lb have basic character and can beconverted into their pharmaceutically acceptable acid addition salts.Such salts comprise, for example, those with organic acids such asoxalic acid, citric acid, acetic acid, lactic acid, maleic acid andtartaric acid, or with inorganic acids such as hydrochloric acid,hydrobromic acid or sulfuric acid. The pharmaceutically acceptable acidaddition salts are crystalline, solid substances which are soluble inwater, somewhat less soluble in polar solvents such as methanol, ethanoland the like, and relatively insoluble in non-polar solvents such asbenzene, ether and petroleum ether.

As previously mentioned, the compounds of Formulas Ia and lb possess anexcellent antidepressive action and are therefore usefulantidepressants. To demonstrate the antidepressent activity inwarm-blooded animals, a compound of Formula Ia or Ib, as the testcompound, was

injected subcutaneously in the doses set out hereinafter to groups of 10mice each. Sixteen hours later, the animals received 5 mg./kg. of2-hydroxy-2-ethyl-3isobutyl-9,l0- dimethoxy 1,2,3,4,6,7 hexahydro llbHbenzo[a] quinolizine hydrochloride (substance A) injectedsubcutaneously. The same dosage was administered to a control group of 10 non-pretreated mice. After 30 minutes, ethanol in a dosage of 3.75g./kg. was administered intraperitoneally to all animals, as Well as tothe control group of 10 mice. The average duration of sleep wasdetermined in each group of mice. The percentage reduction of theduration of sleep compared to the ethanol-sleep potentiated by substanceA served as a measure of antidepressive activity.

Results obtained utilizing the compounds of Formula Ta or 112 as thetest compounds in the foregoing procedure are setforth hereinbelow inTable I:

The low toxicity of the compounds of Formulas Ia and Ib is illustratedby the acute toxicity in mice (24-hour values) set forth hereinbelow inTable HI.

hydrochloride 1, 000-2, 000 1-chloro-5-(3-djmethylaminopropyl)-H-dibenzo- [a,dlcycloheptene N -oxide hydrochloride 60-120 1, 0002, 000

l-chloro-IO,11-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cyc1oheptene N-oxide oxalate Amitrip tyline The absenceor only slight anticholinergic action can be shown by the absence ofsalivation inhibition in rabbits. The salivation was increased inrabbits in light urethane narcosis with pilocarpine injection and theamount of saliva was measured at 5-minute intervals. 1-chloro-S-(3-dimethylaminopropylidene) 5H dibenzo [a,d] cyclohepteneN-oxide hydrochloride did not inhibit the salivation at 1 and 3 mg./kv.iv. and only slightly at 6 mg./ kg. Upon the administration of theaforementioned compound, as well as by the administration of l-chloro-10,1l-dihydro-5-(3-dimethylaminopropylidene) 5H dibenzo[a,dJcycloheptene N-oxide hydrochloride, l-chloro- 5-(3-dimethylaminopropyl)5H dibenzo[a,d]cycloheptene N-oxide hydrochloride,l-chloro-l0,ll-dihydro-S- (3-dimethylaminopropyl) 5Hdibenzo[a,d]cycloheptene N-oxide oxalate or1-fiuoro-10,11-dihydro-5-(3-dimethylaminopropylidene) 5Hdibenzo[a,d]cycloheptene N-oxide hydrochloride, there is observed alesser decrease in salivation than upon the administration in a similarmanner of Amitriptyline.

The compounds of Formulas Ia and Ib can be used as medicaments; forexample, in the form of pharmaceutical preparations which contain themor their pharmaceutically acceptable acid addition salts in admixtureWith pharmaceutical, inert carriers suitable for enteral, for example,oral, or parenteral application. Such carriers comprise organic orinorganic substances, such as, for example, water, gelatin, lactose,starches, magnesium stearate, tale, vegetable oils, gum arabic,polyalkyleneglycols and the like. The pharmaceutical preparations can bein solid form, for example, as tablets, dragees, suppositories,capsules, or in liquid form, for example, as solutions, suspensions oremulsions. They may be sterilized and/or contain additives such aspreserving, stabilizing, wetting or emulifying agents, salts for varyingthe osmotic pressure or buffers. They can also contain additionaltherapeutically valuable substances.

Convenient pharmaceutical dosage forms contain about 1 to 200 mg. of acompound of Formula 112 or lb. Convenient oral dosages are in the rangeof about 0.1 mg./ kg. per day to about 5 mg./kg. per day. Convenientparenteral dosages are in the range of about 0.01 mg./ kg. per day toabout 1 mg./kg. per day. However, the aforementioned ranges areexemplary and can be varied upwards or downwards, depending upon therequirements of the warm-blooded animal being treated.

The following examples further illustrate the invention. Alltemperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of l-chloro 10,11dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene N oxldeoxalate 10 g. ofl-chloro-10,1l-dihydro-S-(3-dimethylaminopropyl)-5H-dibenzo[a,dJcyclohepteneare dissolved in 100 ml. of methanol, and, thereafter, treated dropwisewith 10.6 g. of aqueous hydrogen peroxide solution. The reaction mixtureis stirred at room temperature for an additional 24 hours, whereupon,with cooling, the excess of hydrogen peroxide is decomposed by additionof platinum black. Subsequently, the reaction mixture is filtered,concentrated under reduced pressure and the residue dissolved inethanol. The ethanolic solution is treated with a solution containing6.5 g. of oxalic acid in ml. of ether and the precipitate which forms isremoved by filtration to yield 1-chloro-l0,ll-dihydro-S-(3-dimethylaminopropyl) 5H dibenzo[a,d]cycloheptene N-oxide oxalatehaving a melting point of 128 C.

The 1-chloro-10,11-dihydro 5 (3 dimethylaminopropyl) 5Hdibenzo[a,d]cycloheptene employed as the starting material can beprepared as follows:

86.6 g. of Gilman alloy or magnesium turnin gs are heated under refluxconditions in 800 ml. of absolute ether with a trace of iodine. Asolution containing 390 g. of dimethylaminopropyl chloride in 500 ml. ofabsolute tetrahydrofuran is subsequently added dropwise over a period of2 hours. The mixture is heated under reflux conditions for an additional3 hours. A solution containing 242.7 g. of l-chloro-10,l l-dihydro 5Hdibenzo[a,d]cyclohepten- 5-one in 500 ml. of absolute tetrahydrofuran isadded dropwise over a period of 15 minutes to the suspension obtained.The mixture is cooled to 15 C. and heated under reflux conditions for anadditional 12 hours. Subsequently, the reaction mixture is cooled to 15and hydrolyzed with 500ml. of saturated ammonium chloride solution,filtered and rinsed with methylene chloride. The filtrate is dried withsodium sulfate and evaporated under reduced pressure. The residualyellow substance is recrystallized from 6000 ml. of high-boilingpetroleum ether to yield l-chloro-l0,ll-dihydro-5-(3-dimethylaminopropyl)- S-hydroxy 5Hdibenzo[a,d]cycloheptene having a melting point of l3l-132 C.

500 g. of 1-chloro-10,l1-dihydro 5 (3 dimethylaminopropyl) 5 hydroxy 5Hdibenzo[a,d]cycloheptene, 437 g. of red phosphorus, 4000 ml. of glacialacetic acid and 2160 ml. of 57% hydroiodic acid are heated under refluxconditions in an argon atmosphere for 3 hours. The suspension isfiltered. The filtrate is washed with 2000 ml. of boiling water andsubsequently cooled to 20 C. The crystals which separate out are removedby decantation and the mother liquor is concentrated under reducedpressure. The combined residues are suspended in 15,000 ml. of water,cooled with ice and, with stirring, adjusted to pH 10-12 withconcentrated caustic soda. The solution is extracted with 4000 ml. ofmethylene chloride. The organic phase is successively washed withsaturated sodium chloride solution and sodium thiosulfate solution,dried with sodium sulfate and evaporated under reduced pressure. Theresidue is dissolved in 2000 ml. of ether, insoluble portions areremoved "by filtration and subsequently evaporated to yield yellow, oilyl-chloro- 10,11 dihydro 5 (3 dimethylaminopropyl) 5H-dibenzo[a,d]cycloheptene. The hydrochloride of this compoundcrystallizes from acetone/ether and has a melting point of 149-153 C.

EXAMPLE 2 Preparation of l-chloro-S- 3-dimethylaminopropylideneSH-dibenzo [a,d] cycloheptene N-oxide hydrochloride 835 g. ofl-chloro-S-(3-dimethylaminopropylidene) -5H- dibenzo[a,d] cycloheptene(isomeric mixture 1:1) are dissolved in 4000 ml. of methanol. 920 g. of30% aqueous hydrogen peroxide solution are added dropwise to thissolution over a period of 60 minutes and stirred at room temperature foran additional 64 hours. The reaction mixture is subsequently poured on6000 ml. of ice-water and 1200 ml. of 25% aqueous ammonia solution andextracted with three 2000 ml. portions of methylene chloride. Thecombined extracts are washed with water, until no more hydrogen peroxideis detectable, filtered and made acidic with methanolic hydrochloricacid. The solution is evaporated under reduced pressure, dissolved in1500 ml. of methanol and filtered. The residue is rinsed with a further500 ml. of methanol and the combined filtrates are treated with 60007000ml. ether. After standing at -2 C.,

9 l-chloro-S-(3-dimethylaminopropylidene) 5H dibenzo [a,d]cyclohepteneN-oxide hydrochloride is obtained in crystalline from having a meltingpoint of 1707176 C.

i The reaction of both components mentioned above can also beefiected asfollows:' i i 4 1 500g. of, l-chloro-S-(3-dirnethylaminopropylidene)5H4dibenzo[a,d] cycloheptene (isomeric mixture 1:1) are dissolved in 2500m1. of methanol. The-solution is allowed to cool to 0-5 C. 550g. of anaqueoushydrogen peroxide solution are added dropwise over a period vof60 minutes and theresulting reaction mixture isstirred at 20 C. forabout 60 hours. The reactionmixture is subsequently poured into3500ml... of ice water and 680 ml. of 25% aqueous ammonia solution andextracted with 2000 ml. portions of .methylene chloride. The combinedextracts are washedfwith l000 ml. of water until no trace of hydrogenperoxidefremains, acidified with methanolic hydrochloric acid andconcentrated under reduced pressure at 50 C."The residue is two or threetimes concenrated with 500 ml. absolute benzene and subsequently driedunder reduced pressure for about 2-3 hours at 40 C. The yellow, viscousresidue is dissolved in 2000 ml. of absolute methanol and treated with5000 ml. of absolute ether for thepurposepf crystallization. Aftertheaddition Qfdecolorizing carbon, theentire mixture isfiltered and treatedwith2000 ml of absolute ether. After inoculation, and scratching,the'solutionisallowed to stand at -2"- C. for 48 hours. Then, afterfiltrationand washingwithether, there is I obtained;I-chloro-S-(g-dimethylaminopropylidene)-H-'-dibenzo [a,d] 'cyclohepteneN oxide hydrochloride in the crystalline form, having a melting point of175 176 C. From the mother liquor, through concentration and renewedcrystallization, there is obtained a second crystalline portion, havinga melting point of 169- 173 C.

The l chloro-5'-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cyclohepteneused as the starting material can be prepared as follows:

l7 g. of magnesiu m and 8.5 g. of dimethylaminopropyl chloride arereacted according to the procedure set forth in Example 1. The resultingGr'ignard compound is then treatedwith a solution containing 52 g. ofl-chloro-SH- diberrz'o[a,d]cycloheptenfi-one in 50'0l r'nl; of absolutetet? rahydrofuran. The working up proceeds the same manner as set forthin Example l in; the case 'offthe preparation of.1-chloro-l0,1Ldihydro-S-( 3 dimethylaminopropyl) ,5hydroXy-SH-dibenzo[a,d]cycloheptene to yield 1-chloro-5-(3-dimethylaminopropyl) 5 -jhy'drolxy- SH-dibenzo[a,d]cycloheptenehaving a melting point of 134"435 C. The hydrochloride salt preparedtherefrom has a melting point of 2 2 6 227 C. after recrystallizationfrom methanol/ether. Y l0 g. of 1 -ch1oro 5 (Bi-dimethylaminopropyl) '5hydroxy,-5 H-dibenzo[a,d] cycloheptene are heated under refluxconditions for 1 hour in 50 ml.' jof absolute ethanol and 11 ml. of 30%ethanolic hydrochloric acid. The reaction mixture is evaporated underreduced pressure, taken up in water, washed with ether, made" alkalinewith 2-N caustic soda and shaken out with methylene chloride. Theorganic phase iswashed with water, dried over sodium sulfate andevaporated to yield 1-chloro-5-(3-dimethylaminopropylidehe) 5H-dibenzo[a,d] cycloheptene as a viscous oil. This compoundcomprises amixture of the two isomers in the ratio of about '1: 1'. Thehydrochloride, whichjc'an bepr'pared by=treatment with methanolichydrochloric acid, has amelting pointof 208-210 C. afterrecrystallization fro'methanol/ether. 1

v EXAMPLE Preparation of 1 chloro--l0,ll-dihydro-5-(3-dimethylaminopropylidene) 5H dibenzo[a,d]cycloheptene N- oxide hydrochloride If in Example ,2 1-chloro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene .is replaced byan equivalent amount of lchloro-10,1l-dihydro-5-(3-dimethylaminopropylidene) 5H"--dibenzo[a,d]cycloheptene, under otherwise similar conditions,1-chloro-l0,-1ldihydro 5 (3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene N-oxide hydrochloride having a melting point of165-168 C. is obtained asthe end-product.

The'l-chloro-10,11-dihydro -.5(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene employed aboveas the starting material can be prepared as follows: i

10 g. of l-chloro-l0,ll-dihydro-S-(3-dimethylaminopropyl) 5hydroxy-5H-dibenzo[a,d]cycloheptene are heated underreflux conditionsfor 1 hour with 50 ml. of ethanol and 11 ml. of 30% ethanolichydrochloric acid. Then, the reaction mixture is evaporated underreduced pressure and subsequently recrystallized frornmethanol/ ether toyield l-chloro-10,1l-dihydro-S-(Ii-dimethylaminopropylidene -5H-dibenzo[a,d] cycloheptene hydrochloride having a melting point of 208-210" C.This .compound comprises amixture of the twogeornetric isomers +5, inthe ratio of 1:1. I

. EXAMPLE 4 Preparation of l-chloro-S-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene N-oxide hydrochloride 8.3 g. of1-chloro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene aredissolved in ml. of methanol and treated with 9.05. g. of 30% aqueoushydrogen peroxide solution. The reaction mixture is stirred at 50 C. for41 hours. After decomposition of the excess of hydrogen peroxide byaddition of platinum black, the reaction mixture is filtered, acidifiedwith 30% methanolic hydrochloric acid and concentrated under reducedpressure. The residue crystallizes from acetone to yield 1-chlo ro 5(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene N-oxidehydrochloride having a melting point of l79l81 C.

The 1 chloro-5-(3-dimethylaminopropyl)-5H-dibenzo [a,d]cycloheptene usedas the starting material can be prepared as follows:

200 g. of l-chloro-5H-dibenzo[a,d]cyclohepten-S-one are dissolved in1000 ml. of dioxane and treated with a solution containing 69 g. ofsodium borohydride in 200 ml. of water. After stirring for 12 hours atroom temperature, the reaction mixture is concentrated under reducedpressure and the residue is partitioned between water and ether. Theethereal solution is washed, dried and evaporated to yield1-chloro5-hydroxy-SH-dibenzo [a,d]cycloheptene, which afterrecrystallization from ether/ petroleum ether has a melting point of 143l44 C.

70 g. of 1-chloro-5-hydroxy-SH-dibenzo[a,d]cycloheptene are dissolved in250 ml. of absolute benzene and heated under reflux conditions for 2hours with ml. of thionyl chloride. The reaction mixture is evaporatedunder reduced pressure and the residue crystallized from carbontetrachloride. The crystals which form are removed by filtration andwashed with petroleum ether to yield1,5-dichloro-5H-dibenzo[a,d]cycloheptene having a melting point of 143-l44 C.

5.6 g. of magnesium turnings are suspended in 100 ml. of aboslutetetrahydrofuran and treated with a trace of iodine and methyl iodide. Asolution containing 26 g. of dimethylaminopropyl chloride in 100 ml. oftetrahydrofuran is added dropwise to this mixture over a period of about20 minutes under reflux conditions. The mixture is boiled for, anadditional 3 hours. After cooling to 20 C., a solutioncontaining 25.2 g.of 1,5-dichloro-5H-dibenzo[a,d]cycloheptene in 250 ml. oftetrahydrofuran is added dropwise over a period of 15 minutes. Themixture is subsequently heated under reflux condtions for 15 hours,cooled and hydrolyzed with 200 ml. of saturated ammonium chloridesolution. Thereafter, the mixture is filtered and rinsed with methylenechloride. The filtrate is dried with sodium sulfate and evaporated underreduced pressure to yieldl-chloro-S-(Ii-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene as aviscous oil having a boiling point of about 160 C./0.01 mm. Its maleamicacid salt has a melting point of 146-147 C.

EXAMPLE 5 Preparation of 1-ch1oro-10,1l-dihydro 5(3-dimethylaminopropylidene) 5H dibenzo[a,d]cycloheptene N- oxidehydrochloride 5 g. of1-chloro-10,ll-dihydro-S-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cyclohepteneN-oxide hydrochloride are dissolved in 20 ml. of absolute methanol andheated under reflux conditions for 2 hours with 2 ml. of 24% (W./v.)methanolic hydrochloric acid. After cooling, the reaction mixture istreated with ether to crystallize 1chloro-10,1l-dihydro-S-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cyclohepteneN-oxide hydrochloride having a melting point of 163 --165 C.

The 1-chloro-10,11-dihydro(3-dirnethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene N-oxidehydrochloride used as the starting compound can be prepared as follows:

40 g. of1-chloro-10,l1-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cyclohepteneare dissolved in 1000 ml. of methanol, treated with 61 ml. of 30%aqueous hydrogen peroxide solution and stirred at room temperature for160 hours. The excess of hydrogen peroxide is subsequently decomposed bycautious addition of platinum black. Thereafter, the reaction mixture isfiltered and evaporated under reduced pressure. The residue is acidifiedwith methanolic hydrochloric acid. After the addition of ether,crystalline 1-chloro-10,11-dihydro- 5(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]

cycloheptene N-oxide hydrochloride precipitates, having a melting pointof 164 -166" C.

EXAMPLE 6 Preparation of 1-chloro-5-(3-dimethy1aminopropylidene)-SH-dibenzo [a,d] cycloheptene N-oxide hydrochloride If, in the processaccording to Example 5, 1-chloro-5- (3 dimethylaminopropyl)5-hydroxy-5H-dibenzo[a,d] cycloheptene N-oxide hydrochloride is employedin place of 1-chloro-l0,l 1-dihydro5-( 3-dimethylaminopropyl) -5-hydroxy-SH-dibenzo[a,d]cycloheptene N-oxide hydrochloride, underotherwise similar conditions, there is obtained 1chloro-S-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cyclohepteneN-oxide hydrochloride which has a melting point of 172-174 C., afterrecrystallization from methanol/ ether.

The 1 chloro-5-(3-dimethylaminopropyl)-5-hydroxy-SH-dibenzo[a,d]cycloheptene N-oxide hydrochloride employed as thestarting material in the above reaction can be prepared as follows:

2 g. of l-chloro-S-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene are dissolved in 60 ml. of methanol andtreated with 2.1 g. of 30% aqueous hydrogen peroxide solution. Themixture is stirred at 50 C. for 35 hours. The crystals which separateout after cooling to l0 C., are removed by filtration and washed withether to yield1-chloro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cyclohepteneN-oxide having a melting point of 161 165 C. This compound is dissolvedin ether and treated with methanolic hydrochloric acid to yield1-chloro-5-(3-dimethylaminopropyl)-5-hydroxy-SH-dibenzo[a,d]cycloheptene N-oxide hydrochloride having a melting pointof 174l77 C. after recrystallization from methanol/ ether.

EXAMPLE 7 Preparation of 1- fluoro 10,11dihydro-5-(3-dimethylaminopropylidene) 5H-dibenzol[a,d]cycloheptene N-oxide hydrochloride 3 g. of 1 fluoro10,11-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cyclohepteneare dissolved in 30 ml. of methanol in an argon atmosphere and treatedwith 3.5 g. of 30 percent aqueous hydrogen peroxide solution. Themixture is maintained at 50 C. with stirring for 24 hours. After coolingto 0 C., the excess of hydrogen peroxide is decomposed by addition ofplatinum black. The solution is filtered, acidified with methanolichydrochloric acid and evaporated under reduced pressure. The residue iscrystallized from methanol/ ether. The crystals which form are removedby filtration and dried under reduced pressure at C. to yield 1- fluoro10,11 dihydro-5-(3-dimethylaminopropylidene)- 5H-dibenzo[a,d]cycloheptene N-oxide hydrochloride, having a melting point of 166l68 C.The compound comprises a mixture of the two 1x and fi-isomers in theratio of about 1:1.

The1-fluoro-10,11-dihydro5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cyclohepteneemployed as the starting compound can be prepared as follows:

14.8 g. of powdered phthalic acid anhydride, 18.5 g. ofo-fluorophenylacetic acid and 0.5 g. of freshly melted sodium acetateare heated at 235-240 C. for 3 hours and the resulting water is removedby distillation. The hot reaction mixture is poured into a mortar andpulverized. The crude product is recrystallized from acetone/petroleumether to yield o-fluorobenzylidenephthalide, having a melting point of148 151 C.

72.6 g. of o-fluorobenzylidenephthalide, 55.0 g. of red phosphorus and450 ml. of hydroiodic acid (d=1.75) are heated under reflux conditionsin an argon atmosphere for 24 hours. The reaction mixture is cooled,treated with 500 ml. of water and filtered. The residue is warmed to 80C. with'2N caustic soda and again filtered. The alkaline solution isacidified, extracted with methylene chloride, washed with Water, driedand concentrated. The residual solid is recrystallized fromacetone/low-boiling petroleum ether to yield white crystals of2-(o-fluorophenethyl)benzoic acid having a melting point of 93 94 C.

280 g. of polyphosphoric acid is heated to C. 70.0 g. of.2-(o-fluorophenethyl)benzoic acid are then added at once in an argonatmosphere and the reaction mixture is subsequently maintained at C. for3 hours. The hot reaction mixture is poured onto ice-water and extractedWith ether. The ethereal extracts are washed with water, 2-N sodiumhydroxide and again with water until neutral, dried over sodium sulfate,filtered and concentrated. The residue is distilled under stronglyreduced pressure, whereby a yellow oil is obtained which graduallycrystallizes on standing to yield 1-fluoro-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-S-one, having a melting point of 6465 C.

19.1 g. of Gilman alloy and a trace of iodine are suspended in 150 ml.of absolute ether and reacted with 88 g. of dimethylaminopropyl chloridein 200 ml. of tetrahydrofuran as in Example 1. A solution containing 50g. of 1 fluoro 10,11 dihydro5H-dibenzo[a,d]-cycl0- hepten-S-one in 250ml. of tetrahydrofuran is added dropwise at 20 C. over a period of 1hour to the resulting suspension. The mixture is heated under refluxconditions for an additional 15 hours and, after cooling, hydrolyzedwith saturated ammonium chloride solution. The reaction mixture isfiltered, rinsed with methylene chloride, dried with sodium sulfate andevaporated under reduced pressure to yield l-fiuoro 10,11 dihydro5-(3-dime'thylaminopropyl) 5-hydroxy-5H-dibenzo[a,d]cycloheptene, whichafter crystallization from high-boiling petroleum ether, has a meltingpoint of 115 117 C.

15 g. of l-fiuoro-IO,1l-dihydro-S-(3-dimethylaminopropyl) 5hydroxy-SH-dibenzo[a,d]cycloheptene are heated under reflux conditionsfor 2 hours with 100 ml. of absolute ethanol and 12 ml. of 30 percentethanolic hydrochloric acid. Thereafter, the mixture is evaporated underreduced pressure. The working up is effected in the same manner asstated in Example 1, whereby l-fluoro- 10,11 dihydro5-(3-dimethylaminopropylidene)-5H- dibenzo[a,d]cycloheptene is obtained.Its hydrochloride salt has a melting point of 187200 afterrecrystalliza- 13 tion from methanol/ether. The compound comprises amixture of the two and fi-isomers.

EXAMPLE 8 Preparation of 1 chloro10,1l-dihydro-(3-dimethylaminopropylidene) 5H dibenzo [a,d]cyclohepteneN- oxide hydroiodide 0.2 g. l chloro 10,1l-dihydro-S-(3-N-hydroxy-N-methylaminopropylidene) SH-dibenzo[a,d]cycloheptene is allowed to standat room temperature with a solution containing 0.97 g. methyl iodide in500 ml. of acetone for one hour. After dehydration under reducedpressure, there is obtained1-chloro-10,1I-dihydro-S-(B-dimethylaminopropylidene) 5Hdibenzo[a,d]cycloheptene N- oxide hydroiodide, which aftercrystallization from methanol/ether has a melting point of 103104 C.After neutralization with sodium hydroxide solution and reaction of thebase which is released with ethanolic hydrochloric acid, there isobtained the corresponding hydrochloride, which has a melting point of165 -168 C.

The 1 chloro 10,11 dihydro-5-(3-N-hydroxy-N- methylaminopropylidene)5H-dibenzo[a,d] cycloheptene employed as the starting material can beprepared as follows:

To 14 g. of Gilman alloy in 100 ml. of absolute ether, after theaddition of a trace of iodine or methyl iodide, there is added dropwiseover a period of about 30 minutes under reflux conditions a solutioncontaining 45.6 g. of 1-chloro-3-methoxypropane in 300 ml. of absoluteether. The reaction mixture is heated for an additional 3 hours. Aftercooling to 20 C., a solution containing 48.5 g. of 1 chloro10,1l-dihydro-SH-dibenzo[a,d]cyclohepten- 5-one in 160 ml. oftetrahydrofuran is added over a period of 30 minutes. Subsequently, themixture is heated under reflux conditions for 12 hours, hydrolyzed withcooling, with 150 ml. of saturated ammonium chloride solution, filtered,rinsed with chloroform, dried with sodium sulfate and evaporated toyield 1-chloro-10,11-dihydro 5 (3 methoxypropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene, which has a melting point of 80-81 C. afterrecrystallization from ether/petroleum ether.

53.3 g. of 1 chloro 10,11-dihydro-5-(3methoxypropyl) 5hydroxy-SH-dibenzo[a,d]cycloheptene are heated under reflux conditionsfor 1 hour in 250 ml. of methanol and 53 ml. of 30 percent methanolichydrochloric acid. Thereafter, the mixture is evaporated under reducedpressure, taken up in ether, washed with Water, dried with sodiumsulfate and again evaporated to yield 1 chloro 10,11dihydro-5-(3-methoxypropylidene)- SH-dibenzo[a,d]cycloheptene as ayellow oil.

48.5 g. of1-chloro-10,1l-dihydro-S-(3-meth0xypropylidene)-5H-dibenzo[a,d]cyclohepteneare dissolved in 150 ml. of methylene chloride, cooled to C. and treatedover a period of 15 minutes with a solution containing 30 g. of borontrichloride in 150 ml. of methylene chloride. The reaction mixture isstirred at room temperature for an additional 19 hours, then poured ontoice-water, extracted with methylene chloride, washed with water anddried over sodium sulfate. After evaporation, l-chloro- 10,11 dihydro 5(3 chloropropylidene)-5H-dibenzo [a,d]cycloheptene is obtained as ayellow-orange oil which slowly crystallizes out, and has a melting pointof 5153 C.

A mixture of 20 g. of 1-chloro-l0,ll-dihydro-5-(3-chloropropylidene)-5H-dibenzo[a,d]cycloheptene, 80 ml. of absolutemethanol and 30 g. of methylamine is heated at 120 for 12 hours in anautoclave under a nitrogen pressure of 6-atmospheres. The solution issubsequently evaporated under reduced pressure and the yellow, oilyresidue is treated with methanolic hydrochloric acid whereby l chloro10,1l-dihydro-S-(S-methylaminopropylidene) 5H dibenzo[a,d]cycloheptenehydrochloride precipitates. This compound has a melting point of 209210C. after recrystallization from methanol/ 14 ether. It comprises amixture of the aand [S -isomers in the ratio of about 3:2.

The free base is obtained from the 1-chloro-10,11-dihydro 5 (3methylaminopropylidene) SH-dibenzo [a,d]cycloheptene hydrochloride byneutralization with aqueous sodium hydroxide solution. The free base isdissolved in 300 ml. of ether and treated dropwise at -5 C. over aperiod of 45 minutes with a solution containing 6.65 g. of benzoylperoxide in ml. of ether and 30 ml. of chloroform. The mixture isstirred at 5 to 0 C. for 3 hours, whereupon a precipitate graduallyforms. The precipitate is removed by filtration and washed with ether.The ethereal solution is Washed with dilute hydrochloric acid, then withsodium bicarbonate solution and water, dried over sodium sulfate andevaporated whereby oily 1-chloro-10,ll-dihydro-S-(3-benzolyloxy- Nmethylaminopropylidene) 5H dibenzo[a,d]cycloheptene is obtained.

10 g. of 1 chloro 10,11 dihydro 5 (3 N- benzoyloxy Nmethylaminopropylidene) 5H dibenzo[a,d]cycloheptene are heated underreflux conditions for an hour with 150 ml. of ethanol and a solutioncontaining 2 g. of potassium hydroxide in 20ml. of water. After cooling,the mixture is filtered and the filtrate is evaporated under reducedpressure. The residue is taken up in ether and the ethereal solution isshaken with dilute hydrochloric acid. The acidic extracts are madealkaline with concentrated ammonia solution, extracted with ether, driedand evaporated to yield l-chloro10,11-dihydro 5 (3 N hydroxy Nmethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene, having a meltingpoint of 109l12 C. after recrystallization from benzene/petroleum ether.The compound comprises a mixture of the geometric isomers in the ratioof about 1:2.

vEXAMPLE 9 Preparation of 1 chloro 10,11 dihydro 5 (3dimethylaminopropyl) 5H dibenzo[a,d]cycloheptene N-oxide hydroiodide 1-chloro -10,11- dihydro 5 (3 N hydroxy N- methylaminopropyl) 5Hdibenzo[a,d]cycloheptene is heated at room temperature with a solutioncontaining methyl iodide in acetone whereby 1 chloro 10,11- dihydro 5 (3dimethylaminopropyl) 5H dibenzo [a,d] cycloheptene N-oxide hydroiodideis obtained as the reaction product. After neutralization with sodiumhydroxide solution and treatment of the released base in ethanolicsolution with a solution of oxalic acid in ether, the correspondingoxalate is obtained, which has a melting point of 128 C.

The 1 chloro 10,11 -dihydro 5 (3 N hydroxy- N methylaminopropyl) 5Hdibenzo[a,d]cycloheptene employed as the starting material can beprepared as follows:

A solution containing 102.5 g. of 1 chloro 10,11- dihydro 5 (3dimethylaminopropyl) 5H dibenzo [a,d]cycloheptene in 500 ml. ofmethylene chloride is added dropwise to a solution containing 55 g. ofcyanogen bromide in 500 ml. of methylene chloride. The mixture isstirred at room temperature for 12 hours and subsequently poured ontoice-water. The methylene chloride phase is washed with 2-N hydrochloricacid and water, dried with sodium sulfate and evaporated under reducedpressure. The residual yellow oil is crystallized from ether to yield 1chloro 10,11 dihydro 5 -.(3 N cyano N- methylaminopropyl) 5Hdibenzo[a,d]cycloheptene having a melting point of 69 -7l C. Afterre-solution' in benzene/ether, this compound can be further purifiedchromatographically on 500 g. of silica gel.

A mixture of 650 g. of 1 chloro 10,11 dihydro 5- (3 N cyano Nmethylarninopropyl) 5H dibenzo [a,d]cycloheptene, 4000 ml. of glacialacetic, 2000 ml. of water and 1000 ml. of concentrated hydrochloric acidis heated under reflux conditions for 24 hours. Thereafter, the reactionmixture is concentrated under reduced pressure, diluted with 20,000 m1.of ice-cold water and washed with 5000 ml. of methylene chloride. Themixture is made alkaline with concentrated caustic soda and theresulting precipitate is taken up in methylene chloride. Uponconcentration of the methylene chloride solution, there is obtained abrown-red oil which is converted into crystalline 1 chloro 10,11 dihydro(3 methylaminopropyl) 5H dibenzo[a,d]cycloheptene hydrochloride by theaddition of methanolic hydrochloric acid. This compound has a meltingpoint of 168-169 C. after recrystallization from methanol/ether. Thefree base is obtained from the hydrochloride by neutralization withsodium hydroxide solution.

The 1 chloro 10,11 dihydro 5 (3 methylaminopropyl) 5Hdibenzo[a,d]cycloheptene obtained above is treated with benzoyl peroxideaccording to the procedure set forth in Example 8 and the 1 chloro10,11- dihydro 5 (3 N benzoyloxy N methylaminopropyl) 5Hdibenzo[a,d]cycloheptene obtained is boiled with ethanolic causticpotash according to the details of Example 8, to yield 1 chloro 10,11dihydro- 5 (3 N hydroxy N methylaminopropyl) 5H-dibenzo[a,d]cycloheptene as a crystalline powder having a melting pointof 104-105 C.

EXAMPLE 10 Preparation of 1 chloro 10,11 dihydro 5Hdimethylaminopropylidene) 5H dibenzo[a,d]cycloheptene N-oxidehydrochloride 1.8 g. of N,N-dimethylhydroxylamine hydrochloride aredissolved in 10 ml. of nitromethane and treated with 1.6 g. of 95percent sodium methylate solution as well as a solution containing 1 g.of 1 chloro 10,11 dihydro 5 (3 bromopropylidene) 5H dibenzo[a,d]cycloheptene in 6 ml. of nitromethane. The mixture is stirredsubsequently for 24 hours at 3035 C. and concentrated under reducedpressure. The residue is taken up in methylene chloride, washed withwater, dried, acidified with methanolic hydrochloric acid and thereafterevaporated under reduced pressure. Crystallization from methanol/etheryields 1 chloro 10,11 dihydro 5H- (dimethylaminopropylidene) 5Hdibenzo[a,d]cycloheptene N-oxide hydrochloride, having a melting pointof 165 168 C. The starting materials can be prepared according to thefollowing procedure:

To 14 g. of Gilman alloy in 100 ml. of absolute ether, after theaddition of a trace of iodine or methyliodide, is added dropwise asolution containing 45.6 g. of l-chloro- 3-methoxypropane in 300 ml. ofabsolute ether over a period of 30 minutes under reflux conditions. Thereaction mixture is heated for an additional 3 hours. After cooling toabout 20 C., a solution containing 48.5 g. of 1-ch1oro- 10,11 dihydro 5Hdibenzo[a,d]cyclohepten 5 one in 160 ml. of tetrahydrofuran is addedover a 30-minute period. The reaction mixture, thereafter, is heated for12 hours under reflux conditions, hydrolyzed, with cooling, with 150 ml.of saturated ammonium chloride solution, filtered, washed withchloroform, dried with sodium sulfate and evaporated. The resulting1chloro-10,l1-dihydro 5 (3 methoxypropyl) 5 hydroxy 5H-dibenzo[a,d]cycloheptene, has a melting point of 80 81 C. afterrecrystallization from ether/petroleum ether.

1 chloro 10,11dihydro-5-(3-methoxypropyl)-5-hydroxy-SH-dibenzo[a,d]cycloheptene can ina similar manner be reacted with hydrobromic acid in glacial aceticacid. After the splitting off of water, there is obtained 1- chloro10,11 dihydro-5-(3-bromopropylidene)-5H-dibenzo[a,d]cycloheptene, whichfollowing conventional work-up has a melting point of 65 -67 C. Thereaction product comprises.an isomeric mixture (about 60 percenttat-isomer).

16 EXAMPLE 11 Preparation of tablets l-chloro 5 (3dimethylaminopropylidene)- 5H-dibenzo[a,d]cycloheptene N oxidehydrochloride 28.05

Lactose Corn starch 57.95 Talcum 3.40 Magnesium stearate 0.6

The ingredients are intimately mixed with one another and pressed intotablets each weighing 200 mg., which are subsequently coated with ethylcellulose and Carbowax.

We claim:

1. A compound selected from the group consisting of compounds of theformulas and wherein R is chlorine or fluorine and X is ethylene orvinylene, and their pharmaceutically acceptable acid addition salts. 2.A compound in accordance with claim 1 of the formula I cm CHOH OH Nwherein R is chlorine or fluorine and X is ethylene or vinylene,

and their pharmaceutically acceptable acid addition salts.

.3. A compound in accordance with claim 2, wherein X is vinylene.

4. A compound in accordance with claim 3, l-chloro-5-(3-dimethylaminopropylidene) 5H dibenzo[a,d]cycloheptene N-oxide.

5. A compound in accordance with claim 2, wherein X is ethylene.

6. A compound in accordance with claim 5, l-chloro-10,11-dihydro-5-(3-dimethylaminopropylidene) 5H dibenzo [a,d]cyclopheptene N-oxide.

7. A compound in accordance with claim 5, l-fluoro-10,11-dihydro-5-(3-dimethylaminopropylidene) 5H dibenzo[a,d]cyclohepteneN-oxide.

8.-A compound in accordance with claim 1 of the formula HZCHZCHZNwherein R is chlorine or fluorine and X is ethylene or vinylene,

and their pharmaceutically acceptable acid addition salts. 9. A compoundin accordance with claim 8, wherein X is vinylene.

17 18 10. A compound in accordance with claim 9, l-chloro- 14. Acompound in accordance with claim 3, l-chloro-5-(3-dirnethy1amin0propyl) 5H dibenzo[a,d]cyclohep-5-(3-dimethy1aminopropylidene) 5H dibenzo[a,d]cytene N-oxide. clohepteneN-oxide.

11. A compound in accordance with claim 8, wherein X is ethylene. 5References Cited 12. A compound in accordance with claim 11, 1- UNITEDSTATES PATENTS chloro-10,11-dihydro-5 (3-dimethylamin0pr0pyl) 5H di-2,862,968 12/1958 Tiffany 260-570 13 xi iii lii'fg gi 3,299,139 1/1967Pedersen 260-5 70.8 Po 3,372,196 3/1968 Engelhardt 260570.8

1 FOREIGN PATENTS 618,034 2/1949 Great Britain 260570.8 1,447,508 6/1966France 260570.8

/CH3 15 ROBERT V. HINES, Primary Examiner Y1 CHCH2CH2N U S Cl XR Y: 0CH3 wherein R is chlorine or fluorine and X is ethylene or 260343-3,3467, 515 vinylene and one of the symbols Y and Y is hydr0- 20 551 567-5590, 611 618 613 F, gen and the other is hydroxyl, 649 R, 649 P; 424-330and their pharmaceutically acceptable acid addition salts.

